EP0276674A1 - Parenteral solution - Google Patents

Parenteral solution Download PDF

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Publication number
EP0276674A1
EP0276674A1 EP88100279A EP88100279A EP0276674A1 EP 0276674 A1 EP0276674 A1 EP 0276674A1 EP 88100279 A EP88100279 A EP 88100279A EP 88100279 A EP88100279 A EP 88100279A EP 0276674 A1 EP0276674 A1 EP 0276674A1
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Prior art keywords
weight
active pharmaceutical
pharmaceutical ingredient
solution
solvent
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German (de)
French (fr)
Inventor
Wolfgang Dr. Hoederath
Hans Jürgen Dr. Ahr
Klaus Dr. Bühner
Ahmed Dr. Hegasy
Manfred Dr. Winter
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Bayer AG
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Bayer AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/829—Blood
    • Y10S530/83—Plasma; serum

Definitions

  • organic solvents such as propylene glycol, polyethylene glycol, ethanol, glycerin-polyethylene glycol ricinoleate (Cremophor® EL) or polyoxyethylene sorbitan fatty acid ester (Tween®) have been added to formulate parenteral solutions of poorly soluble drugs to increase solubility.
  • solvents can only be used in lower concentrations, since higher concentrations lead to undesirable side effects such as injection pain, thrombophlebitis and venous obliteration.
  • some solvents lead to side effects such as anaphylactic shocks and hemolysis.
  • solubilization described in US Pat. No. 4,158,707 with a combination of bile acid and lipoid has the disadvantage of a limited shelf life of the solubilizers, especially at higher temperatures, and of side effects such as vomiting, hemolysis and cholestasis when administered in higher doses.
  • the present invention now relates to parenteral solutions of poorly soluble medicaments which contain human serum proteins, the human serum proteins serving as crystallization inhibitors.
  • parenteral solutions are essentially intravenous applications with drugs, especially injection and infusion solutions.
  • active substance-containing concentrates are generally used in suitable organic solvents such as 1,2-propylene glycol, glycerol, ethanol, polyethylene glycols with average molecular weights between 200 and 600 and tetrahydrofurfuryl alcohol polyethylene glycol ether in a mixture with water, which is diluted with aqueous human serum protein solutions before application will.
  • Human albumin solutions USP XXI
  • plasma protein fraction solutions USP XXI
  • the serum proteins can also contain ⁇ -, ⁇ - and ⁇ -globulins.
  • the poorly soluble active pharmaceutical ingredients which can be used according to the invention generally have a solubility speed in water between 1 ⁇ g and 10 g, preferably between 10 ⁇ g and 1 g per liter of water.
  • examples include dihydropyridine compounds and pyrazolones and muzolimine.
  • human albumin or plasma protein fraction solutions which can be used according to the invention are commercially available in the form of 5, 20 or 25% solutions and are described in many pharmacopoeias, for example in USP XXI, BP 80 and in Remington's Pharmaceutical Sciences, Mack Publishing Company , Easton Pennsylvania.
  • the parenteral solutions can contain, among other things, auxiliaries and / or carriers, such as N-acetyl-dl-tryptophan, caprylate, acetate, citrate, glucose and electrolytes such as sodium, potassium, calcium, magnesium and chloride, phosphates and hydrogen carbonate
  • auxiliaries and / or carriers such as N-acetyl-dl-tryptophan, caprylate, acetate, citrate, glucose and electrolytes such as sodium, potassium, calcium, magnesium and chloride, phosphates and hydrogen carbonate
  • the parenteral solution according to the invention can be prepared by first dissolving the active pharmaceutical ingredient in an organic solvent and, if appropriate, additionally adding water. This concentrate is then filtered, filled and diluted with human serum protein solution immediately before application.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Parenterale Lösung, enthaltend a) einen schwer löslichen Arzneimittelwirkstoff, b) ein Lösungsmittel bestehend aus (i) 5 - 100 G/V % eines organischen Lösungsmittels und (ii) 0 - 95 G/V % Wasser c) eine 0,5 - 30 G/V %ige wässrige Lösung eines Humanserumproteins sowie übliche Hilfs- und/oder Trägerstoffe, wobei pro ein Gewichtsteil Arzneimittelwirkstoff 1 bis 40.000 Gewichtsteile des Lösungsmittels b) und 1 bis 1.000.000 Gewichtsteile der Humanserumproteinlösung c) vorliegen; sowie ein Verfahren zu ihrer Herstellung.Parenteral solution containing a) a poorly soluble active pharmaceutical ingredient, b) a solvent consisting of (i) 5 - 100 w / v% of an organic solvent and (ii) 0 - 95 w / v% water c) a 0.5 - 30 W / V% aqueous solution of a human serum protein and conventional auxiliaries and / or carriers, 1 to 40,000 parts by weight of the solvent b) and 1 to 1,000,000 parts by weight of the human serum protein solution c) being present per part by weight of the active pharmaceutical ingredient; and a process for their manufacture.

Description

Die parenterale Applikation von Arzneistoffen, im we­sentlichen die intravenöse Applikation, ist nur in ge­löster Form möglich. Daher bereitet die Formulierung von Injektions- und Infusionslösungen bei Arzneistoffen ge­ringer Wasserlöslichkeit regelmäßig Schwierigkeiten.Parenteral administration of drugs, essentially intravenous administration, is only possible in dissolved form. Therefore, the formulation of injection and infusion solutions for drugs with low water solubility regularly presents difficulties.

Im Falle unzureichender Löslichkeit in Wasser wurden bislang bei der Formulierung parenteraler Lösungen schwer löslicher Arzneistoffe organische Lösungsmittel wie Propylenglykol, Polyethylenglykol, Ethanol, Glyce­rin-Polyethylenglykolricinoleat (Cremophor® EL) oder Polyoxyethylensorbitanfettsäureester (Tween®) zur Erhö­hung der Löslichkeit zugesetzt. Die Effektivität dieser Maßnahme wird allerdings dadurch begrenzt, daß Lösungs­mittel nur in niederen Konzentrationen angewendet werden können, da höhere Konzentrationen zu unerwünschten Neben­wirkungen wie Injektionsschmerz, Thrombophlebitis und Venenverödung führen. Darüber hinaus führen einige Lö­sungsmittel zu Nebenwirkungen wie anaphylaktische Schocks und Hämolyse.In the case of insufficient solubility in water, organic solvents such as propylene glycol, polyethylene glycol, ethanol, glycerin-polyethylene glycol ricinoleate (Cremophor® EL) or polyoxyethylene sorbitan fatty acid ester (Tween®) have been added to formulate parenteral solutions of poorly soluble drugs to increase solubility. However, the effectiveness of this measure is limited by the fact that solvents can only be used in lower concentrations, since higher concentrations lead to undesirable side effects such as injection pain, thrombophlebitis and venous obliteration. In addition, some solvents lead to side effects such as anaphylactic shocks and hemolysis.

Eine andere Möglichkeit der Lösungsvermittlung von Arz­neistoffen geringer Wasserlöslichkeit besteht darin, den Arzneistoff in der Fettphase in einer Emulsion zu lösen (US 4 073 943). Dieses Verfahren setzt allerdings eine sehr gute Löslichkeit des Arzneistoffs in physiologisch verträglichen Ölen wie Sojabohnenöl voraus, die nur in den seltensten Fällen gewährleistet ist.Another possibility of mediating the solution of drugs of low water solubility is to dissolve the drug in the fat phase in an emulsion (US Pat. No. 4,073,943). However, this process requires a very good solubility of the drug in physiologically compatible oils such as soybean oil, which is only guaranteed in the rarest of cases.

Die in US 4 158 707 beschriebene Lösungsvermittlung mit einer Kombination aus Gallensäure und Lipoid hat den Nachteil einer begrenzten Haltbarkeit der Lösungsver­mittler, insbesondere bei höheren Temperaturen, sowie von Nebenwirkungen wie Erbrechen, Hämolyse und Cholesta­sis bei Gaben in höheren Dosen.The solubilization described in US Pat. No. 4,158,707 with a combination of bile acid and lipoid has the disadvantage of a limited shelf life of the solubilizers, especially at higher temperatures, and of side effects such as vomiting, hemolysis and cholestasis when administered in higher doses.

Die vorliegende Erfindung betrifft nunmehr parenterale Lösungen von schwer löslichen Arzneimitteln, die Human­serumproteine enthalten, wobei die Humanserumproteine als Kristallisationsinhibitoren dienen.The present invention now relates to parenteral solutions of poorly soluble medicaments which contain human serum proteins, the human serum proteins serving as crystallization inhibitors.

Parenterale Lösungen sind hierbei im wesentlichen intra­venöse Applikationen mit Arzneistoffen, im besonderen Injektions- und Infusionlösungen. Für die erfindungs­gemäßen parenteralen Lösungen verwendet man im allgemei­nen wirkstoffhaltige Konzentrate in geeigneten organi­schen Lösungsmitteln wie 1,2-Propylenglykol, Glycerin, Ethanol, Polyethylenglykolen mit mittleren Molgewichten zwischen 200 und 600 und Tetrahydrofurfurylalkoholpoly­ethylenglykolether im Gemisch mit Wasser, die mit wäß­rigen Humanserumprotein-Lösungen vor Applikation ver­dünnt werden. Als Humanserumprotein-Lösungen werden vorzugsweise Humanalbumin-Lösungen (USP XXI) oder Plasma-Protein-Fraktion-Lösungen (USP XXI) eingesetzt, wobei letztere in aller Regel die Wirkstoffpräzipitation länger dauernd und auch bei höherer Konzentration des Arzneistoffes verzögern. Die Serumproteine können neben Albumin auch α-, β- und γ-Globuline enthalten.Parenteral solutions are essentially intravenous applications with drugs, especially injection and infusion solutions. For the parenteral solutions according to the invention, active substance-containing concentrates are generally used in suitable organic solvents such as 1,2-propylene glycol, glycerol, ethanol, polyethylene glycols with average molecular weights between 200 and 600 and tetrahydrofurfuryl alcohol polyethylene glycol ether in a mixture with water, which is diluted with aqueous human serum protein solutions before application will. Human albumin solutions (USP XXI) or plasma protein fraction solutions (USP XXI) are preferably used as human serum protein solutions. the latter, as a rule, delaying the active ingredient precipitation for a longer time and also with a higher concentration of the pharmaceutical substance. In addition to albumin, the serum proteins can also contain α-, β- and γ-globulins.

Die Erfindung betrifft somit eine parenterale Lösung enthaltend

  • a) einen schwer löslichen Arzneimittelwirkstoff
  • b) ein Lösungsmittel bestehend aus
    • (i) 5 - 100 G/V % eines organischen Lösungsmit­tels oder eines Gemisches organischer Lösungs­mittel und
    • (ii) 0 - 95 G/V % Wasser
  • c) eine 0,5 - 30 G/V %ige wässrige Lösung eines Human­serumproteins
sowie übliche Hilfs- und/oder Trägerstoffe,
wobei pro ein Gewichtsteil Arzneimittelwirkstoff 1 bis 40.000 Gewichtsteile, bevorzugt 25 bis 30.000 Gewichts­teile des Lösungsmittels b) und 1 bis 1.000.000 Ge­wichtsteile, bevorzugt 50 bis 40.000 Gewichtsteile der Humanserumproteinlösung c) vorliegen.The invention thus relates to a parenteral solution containing
  • a) a poorly soluble active pharmaceutical ingredient
  • b) a solvent consisting of
    • (i) 5-100 w / v% of an organic solvent or a mixture of organic solvents and
    • (ii) 0-95 w / v% water
  • c) a 0.5-30% w / v% aqueous solution of a human serum protein
as well as usual auxiliaries and / or carriers,
wherein 1 to 40,000 parts by weight, preferably 25 to 30,000 parts by weight of the solvent b) and 1 to 1,000,000 parts by weight, preferably 50 to 40,000 parts by weight of the human serum protein solution c) are present per one part by weight of active pharmaceutical ingredient.

Die erfindungsgemäß verwendbaren schwerlöslichen Arznei­mittelwirkstoffe besitzen im allgemeinen eine Löslich­ keit in Wasser zwischen 1 µg und 10 g, bevorzugt zwischen 10 µg und 1 g pro Liter Wasser. Beispielhaft seien Dihydropyridinverbindungen und Pyrazolone und Muzolimin aufgeführt.The poorly soluble active pharmaceutical ingredients which can be used according to the invention generally have a solubility speed in water between 1 µg and 10 g, preferably between 10 µg and 1 g per liter of water. Examples include dihydropyridine compounds and pyrazolones and muzolimine.

Von ganz besonderer Bedeutung sind die Dihydropyridin­verbindungen, insbesondere die mit folgender allgemeiner Formel

Figure imgb0001
in der
R₁ C₁-C₄-Alkyl, gegebenenfalls substituiert durch C₁-C₃ Alkoxy,
R₂ C₁-C₁₀-Alkyl, gegebenenfalls substituiert durch C₁-C₃-Alkoxy, Trifluormethyl, N-Methyl-N-benzyl­amino,
R₃ C₁-C₄-Alkyl, Cyano, Hydroxymethyl und
X 2- bzw. 3-Nitro, 2,3-Dichlor, 2,3 Ringglied be­stehend aus =N-O-N=,
bedeuten.Of particular importance are the dihydropyridine compounds, especially those with the following general formula
Figure imgb0001
 in the
R₁ C₁-C₄-alkyl, optionally substituted by C₁-C₃ alkoxy,
R₂ C₁-C₁₀-alkyl, optionally substituted by C₁-C₃-alkoxy, trifluoromethyl, N-methyl-N-benzylamino,
R₃ C₁-C₄ alkyl, cyano, hydroxymethyl and
X 2- or 3-nitro, 2,3-dichloro, 2,3 ring member consisting of = NON =,
mean.

Ganz besonders in Betracht kommen die Verbindungen der folgenden Tabelle:

Figure imgb0002
The compounds in the following table are particularly suitable:
Figure imgb0002

Darüberhinaus sei als Dihydropyridinverbindung noch 2-­Methyl-4-(4-oxo-2-phenyl-4H-thiochromen-8-yl)-5-oxo-­1,4,5,7-tetrahydrofuro-[3,4-b]-pyridin-3-carbonsäure­ethyl oder -methylester erwähnt.In addition, 2-methyl-4- (4-oxo-2-phenyl-4H-thiochromen-8-yl) -5-oxo-1,4,5,7-tetrahydrofuro- [3,4-b] as dihydropyridine compound -pyridine-3-carboxylic acid ethyl or methyl ester mentioned.

Die erfindungsgemäß einsetzbaren Humanalbumin- oder Plasma-Protein-Fraktion-Lösungen sind im Handel in Form 5, 20 oder 25 %iger Lösungen erhältlich und sind in vielen Pharmakopöen beschrieben, beispielsweise in USP XXI, BP 80 sowie in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton Pennsylvania.The human albumin or plasma protein fraction solutions which can be used according to the invention are commercially available in the form of 5, 20 or 25% solutions and are described in many pharmacopoeias, for example in USP XXI, BP 80 and in Remington's Pharmaceutical Sciences, Mack Publishing Company , Easton Pennsylvania.

Die parenteral Lösungen können unter anderem Hilfs- und/oder Trägerstoffe enthalten, wie N-Acetyl-dl-trypto­phan, Caprylat, Acetat, Citrat, Glukose sowie Elektro­lyte wie Natrium, Kalium, Calcium, Magnesium und Chlo­rid, Phosphate, HydrogencarbonatThe parenteral solutions can contain, among other things, auxiliaries and / or carriers, such as N-acetyl-dl-tryptophan, caprylate, acetate, citrate, glucose and electrolytes such as sodium, potassium, calcium, magnesium and chloride, phosphates and hydrogen carbonate

Außerdem:
Säuren, Basen oder Puffersubstanzen zur pH-Einstellung, Salze, Zucker oder mehrwertige Alkohole zur Isotonisie­rung, Konservierungsmittel wie Benzylalkohol, Chlor­butanol, Antioxidantien wie Sulfite, Acetylcystein oder Ascorbinsäure.Furthermore:
Acids, bases or buffer substances for pH adjustment, salts, sugars or polyhydric alcohols for isotonization, preservatives such as benzyl alcohol, chlorobutanol, antioxidants such as sulfites, acetylcysteine or ascorbic acid.

Die erfindungsgemäße parenterale Lösung kann hergestellt werden, indem man zunächst den Arzneimittelwirkstoff in einem organischen Lösungsmittel auflöst und gegebenen­falls zusätzlich Wasser ergänzt. Dieses Konzentrat wird anschließend filtriert, abgefüllt und unmittelbar vor der Applikation mit Humanserumproteinlösung verdünnt.The parenteral solution according to the invention can be prepared by first dissolving the active pharmaceutical ingredient in an organic solvent and, if appropriate, additionally adding water. This concentrate is then filtered, filled and diluted with human serum protein solution immediately before application.

Die so erhaltenen Lösungen sind zwar häufig deutlich übersättigt, die Wirkstoffpräzipitation wird aber verzögert und tritt meist erst nach einigen Stunden auf.The solutions obtained in this way are often significantly oversaturated, but the active ingredient precipitation is delayed and usually occurs only after a few hours.

VersuchsbeispieleExperimental examples

Injektionslösungen entsprechend dieser Erfindung können wie folgt hergestellt werden:

  • 1. - Konzentrat des unlöslichen Arzneistoffes
          2-Methyl-4-(4-oxo-2-phenyl-4 H-thiochromen-8-yl)-5-­oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridin-3-car­bonsäureethylester wird zu 0,5 in einer Mischung aus 600 g Polyethylenglykol 400 und 200 g Ethanol gelöst unter Rühren und Erwärmen. Nach dem Abkühlen auf 20°C wird der Verdunstungsverlust an Ethanol ergänzt und mit Wasser für Injektionszwecke auf 1 Liter aufgefüllt.
          - Fertige Injektionslösung
          2 ml des oben beschrieben Konzentrates werden mit 8 ml Humanalbumin 5 % oder Plasma-Protein-Fraktion 5 % versetzt und vermischt.
          Die so erhaltene applikationsfertige, übersättigte Lösung ist über einen Zeitraum von mehreren Stunden klar und praktisch frei von Partikeln, da eine Aus­kristallisation durch die Verwendung der Protein­lösung als Verdünnungsmedium verzögert wird. Wird das Wirkstoffkonzentrat mit der entsprechenden Menge Wasser verdünnt, so tritt eine sofortige Aus­fällung des Arzneistoffes ein.
  • 2. - Konzentrat des unlöslichen Arzneistoffes
          1 g Nifedipin wird unter Erwärmen in einer Mischung auf 250 g Ethanol und 250 g Polyethylenglykol 400 gelöst. Nach Abkühlen und Ergänzen der verdunsteten Alkoholmenge wird mit Wasser für Injektionszwecke auf 600 ml aufgefüllt.
          - Fertige Injektionslösung,
          0,6 ml dieses Konzentrates werden mit 2,4 ml Human­albumin 5 %ig oder 2,4 ml Plasma-Protein-Fraktion 5 %ig versetzt und vermischt.
          Es resultiert eine über mehrere Stunden Klare Nife­dipin-Injektionslösung.
  • 3. - Konzentrat des unlöslichen Arzneistoffes
          10 g Nisoldipin werden in einer Mischung aus 3.000 g Ethanol und 3.000 g Polyethylenglykol 400 unter Rühren und Erwärmen gelöst. Nach dem Abkühlen auf Raumtemperature wird der Verdunstungsverlust an Ethanol ergänzt und mit Wasser für Injektionszwecke auf 7 l aufgefüllt.
          - Fertige Injektionslösung
          0,35 ml des oben beschriebenen Konzentrates werden mit 2,7 ml Humanalbumin 5 % oder Plasma-Protein-­Fraktion 5 % versetzt und vermischt.
          Es ergibt sich eine über mehrere Stunden klare Nisoldipin Injektionslösung.
  • 4. -Konzentrat des unlöslichen Arzneistoffes
          10 g Nitrendipin werden in einer Mischung aus 4.000 g Ethanol und 4.000 g Polyethylenglykol 400 unter Rühren und Erwärmen gelöst. Nach dem Abkühlen auf Raumtemperatur wird der Verdunstungsverlust an Ethanol ergänzt und mit Wasser für Injektionszwecke auf 10 l aufgefüllt.
          - Fertige Injektionslösung
          1,0 ml des oben beschriebenen Konzentrates werden mit 4.0 ml Humanalbumin 5 % oder Plasma-Protein-­Fraktion 5 % versetzt und vermischt.
          Es ergibt sich eine über mehrere Stunden stabile Nitrendipin Injektionslösung.
  • 5. -Konzentat des unlöslichen Arzneistoffes
    60 g Muzolimin werden in einer Mischung auf 2.000 g Ethanol und 2.000 g Polyethylenglykol 400 unter Rühren gelöst. Anschließend füllt man mit Wasser für Injektionszwecke auf 5 l auf.
          - Fertige Injektionslösung
          2,5 ml des oben beschriebenen Konzentrats werden mit 2,5 ml Humanalbumin 5 % oder Plasma-Protein-­Fraktion 5 % versetzt und vermischt.
          Es entsteht eine über mehrere Stunden klare Muzo­limin Injektionslösung.
Injection solutions according to this invention can be prepared as follows:
  • 1. - Concentrate of the insoluble drug
    2-Methyl-4- (4-oxo-2-phenyl-4H-thiochromen-8-yl) -5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester is dissolved in 0.5 in a mixture of 600 g of polyethylene glycol 400 and 200 g of ethanol with stirring and heating. After cooling to 20 ° C, the loss of evaporation in ethanol is made up and made up to 1 liter with water for injections.
    - Finished solution for injection
    2 ml of the concentrate described above are mixed with 8 ml of human albumin 5% or plasma protein fraction 5%.
    The ready-to-use, supersaturated solution thus obtained is clear and practically free of particles over a period of several hours, since crystallization is delayed by the use of the protein solution as a dilution medium. If the active substance concentrate is diluted with the appropriate amount of water, the medicinal substance precipitates immediately.
  • 2. - Concentrate of the insoluble drug
    1 g of nifedipine is heated to a mixture of 250 g of ethanol and 250 g of polyethylene glycol 400 solved. After cooling and replenishing the evaporated amount of alcohol, make up to 600 ml with water for injections.
    - finished solution for injection,
    0.6 ml of this concentrate is mixed with 2.4 ml human albumin 5% or 2.4 ml plasma protein fraction 5% and mixed.
    The result is a nifedipine solution for injection that is clear for several hours.
  • 3. - concentrate of the insoluble drug
    10 g of nisoldipine are dissolved in a mixture of 3,000 g of ethanol and 3,000 g of polyethylene glycol 400 with stirring and heating. After cooling to room temperature, the loss of evaporation of ethanol is made up and made up to 7 l with water for injections.
    - Finished solution for injection
    0.35 ml of the concentrate described above is mixed with 2.7 ml of human albumin 5% or plasma protein fraction 5% and mixed.
    The result is a nisoldipine solution for injection that is clear over several hours.
  • 4. -Concentrate of the insoluble drug
    10 g of nitrendipine are dissolved in a mixture of 4,000 g of ethanol and 4,000 g of polyethylene glycol 400 with stirring and heating. After cooling to room temperature, the loss of evaporation in ethanol is made up and made up to 10 l with water for injections.
    - Finished solution for injection
    1.0 ml of the concentrate described above is mixed with 4.0 ml of human albumin 5% or plasma protein fraction 5% and mixed.
    The result is a nitrendipine solution for injection that is stable for several hours.
  • 5. Concentrate of the insoluble drug
    60 g of muzolimine are dissolved in a mixture of 2,000 g of ethanol and 2,000 g of polyethylene glycol 400 with stirring. Then make up to 5 l with water for injections.
    - Finished solution for injection
    2.5 ml of the concentrate described above are mixed with 2.5 ml of human albumin 5% or plasma protein fraction 5% and mixed.
    A muzolimine solution for injection that is clear over several hours is formed.

Claims (5)

1. Parenterale Lösung, enthaltend
a) einen schwer löslichen Arzneimittelwirkstoff
b) ein Lösungsmittel bestehend aus
      (i) 5 - 100 G/V % eines organischen Lösungsmittels oder eines Gemisches organischer Lösungsmittel und
      (ii) 0 - 95 G/V % Wasser
c) eine 0,5 - 30 G/V %ige wässrige Lösung eines Humanserumproteins
sowie übliche Hilfs- und/oder Trägerstoffe,
wobei pro ein Gewichtsteil Arzneimittelwirkstoff 1 bis 40.000 Gewichtsteile des Lösungsmittels b) und 1 bis 1.000.000 Gewichtsteile der Humanserum­proteinlösung c) vorliegen.1. Parenteral solution containing
a) a poorly soluble active pharmaceutical ingredient
b) a solvent consisting of
(i) 5-100 w / v% of an organic solvent or a mixture of organic solvents and
(ii) 0-95 w / v% water
c) a 0.5-30% w / v% aqueous solution of a human serum protein
as well as usual auxiliaries and / or carriers,
wherein 1 to 40,000 parts by weight of the solvent b) and 1 to 1,000,000 parts by weight of the human serum protein solution c) are present per one part by weight of active pharmaceutical ingredient. 2. Parenterale Lösung gemäß Anspruch 1, enthaltend 25 bis 30.000 Gewichtsteile des Lösungsmittels b) und 50 bis 40.000 Gewichtsteile der Humanserumprotein­lösung c) pro 1 Gewichtsteil Arzneimittelwirkstoff.2. Parenteral solution according to claim 1, containing 25 to 30,000 parts by weight of solvent b) and 50 to 40,000 parts by weight of human serum protein solution c) per 1 part by weight of active pharmaceutical ingredient. 3. Parenterale Lösung gemäß Anspruch 1 und 2, enthal­tend einen Arzneimittelwirkstoff mit einer Löslich­keit zwischen 1 µg und 1 g pro Liter Wasser.3. Parenteral solution according to claims 1 and 2, containing an active pharmaceutical ingredient with a solubility of between 1 µg and 1 g per liter of water. 4. Parenterale Lösung gemäß Ansprüchen 1 - 3, enthal­tend als Arzneimittelwirkstoff eine Dihydropyri­dinverbindung oder Pyrazolonverbindung.4. Parenteral solution according to claims 1-3, containing a dihydropyridine compound or pyrazolone compound as the active pharmaceutical ingredient. 5. Verfahren zur Herstellung einer parenteralen Lö­sung, enthaltend
a) einen schwer löslichen Arzneimittelwirkstoff
b) ein Lösungsmittel bestehend aus
      (i) 5 - 100 G/V % eines organischen Lösungsmittels oder eines Gemisches organischer Lösungsmittel und
      (ii) 0 - 95 G/V % Wasser
c) eine 0,5 - 30 G/V %ige wässrige Lösung eines Humanserumproteins
sowie übliche Hilfs- und/oder Trägerstoffe,
wobei pro ein Gewichtsteil Arzneimittelwirkstoff 1 bis 40.000 Gewichtsteile des Lösungsmittels b) und 1 bis 1.000.000 Gewichtsteile der Humanserum­proteinlösung c) vorliegen,
dadurch gekennzeichnet, daß man den Arzneimittel­wirkstoff in einem Lösungsmittel löst und anschlie­ßend eine Lösung eines Humanserumproteins zusetzt.5. A process for preparing a parenteral solution containing
a) a poorly soluble active pharmaceutical ingredient
b) a solvent consisting of
(i) 5-100 w / v% of an organic solvent or a mixture of organic solvents and
(ii) 0-95 w / v% water
c) a 0.5-30% w / v% aqueous solution of a human serum protein
as well as usual auxiliaries and / or carriers,
wherein 1 to 40,000 parts by weight of solvent b) and 1 to 1,000,000 parts by weight of human serum protein solution c) are present per part by weight of active pharmaceutical ingredient,
characterized in that the active pharmaceutical ingredient is dissolved in a solvent and then a solution of a human serum protein is added.
EP88100279A 1987-01-24 1988-01-12 Parenteral solution Withdrawn EP0276674A1 (en)

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DE3702105 1987-01-24
DE19873702105 DE3702105A1 (en) 1987-01-24 1987-01-24 PARENTERAL SOLUTION

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EP0276674A1 true EP0276674A1 (en) 1988-08-03

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JP (1) JPS63192714A (en)
KR (1) KR880008801A (en)
AU (1) AU597139B2 (en)
DE (1) DE3702105A1 (en)
HU (1) HU198381B (en)
IL (1) IL85164A0 (en)
NZ (1) NZ223253A (en)
ZA (1) ZA88442B (en)

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EP0611306B1 (en) * 1991-11-08 1998-07-08 Somatogen, Inc. Hemoglobins as drug delivery agents
HUP9701554D0 (en) 1997-09-18 1997-11-28 Human Oltoanyagtermeloe Gyogys Pharmaceutical composition containing plazma proteins
US6682758B1 (en) 1998-12-22 2004-01-27 The United States Of America As Represented By The Department Of Health And Human Services Water-insoluble drug delivery system
WO2000047187A1 (en) * 1999-02-11 2000-08-17 Kinetana Inc. Serum albumin-based parenteral formulations of polyene macrolides
DE10142416A1 (en) * 2001-08-31 2003-03-20 Molecular And Clinical Drug Re Process for the preparation of solutions
WO2005025507A2 (en) * 2003-09-10 2005-03-24 Synta Phamaceuticals Corp. Dihydropyridine compounds for treating or preventing metabolic disorders
WO2009116557A1 (en) * 2008-03-21 2009-09-24 富士フイルム株式会社 Drug-containing composition
US20150140040A1 (en) * 2010-01-19 2015-05-21 Robert E. Coifman Methods of depositing particles of a substance in a tissue
RU2618456C2 (en) * 2010-12-16 2017-05-03 Плэтформ Брайтворкс Ту, Лтд Pharmaceutical azoles preparation for parenteral injection and methods of production and application for treatment of diseases, sensitive to azole compounds
EP3238709B1 (en) 2011-04-28 2020-07-01 Platform Brightworks Two, Ltd. Improved parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same
CN107412783B (en) 2017-04-28 2020-09-22 中国人民解放军军事医学科学院毒物药物研究所 Preparation method of protein particles coated with water-insoluble medicine

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EP0123850A2 (en) * 1983-03-31 1984-11-07 The Board Of Governors Of Wayne State University Inhibition of tumor growth and metastasis with calcium channel blocker compounds
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AU597139B2 (en) 1990-05-24
HUT47838A (en) 1989-04-28
KR880008801A (en) 1988-09-13
NZ223253A (en) 1990-08-28
AU1032388A (en) 1988-07-28
DE3702105A1 (en) 1988-08-04
IL85164A0 (en) 1988-07-31
JPS63192714A (en) 1988-08-10
HU198381B (en) 1989-10-30
US4842856A (en) 1989-06-27
ZA88442B (en) 1988-07-22

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